EP0089426A1

EP0089426A1 - 2-Amino-6-biphenylacetic acids

Info

Publication number: EP0089426A1
Application number: EP82301438A
Authority: EP
Inventors: David Allan Walsh
Original assignee: AH Robins Co Inc
Current assignee: AH Robins Co Inc
Priority date: 1979-07-12
Filing date: 1982-03-19
Publication date: 1983-09-28
Also published as: AU553122B2; EP0089426B1; AU8180982A; JPH0249298B2; JPS58183653A; CA1173853A

Abstract

Novel 2-amino-6-biphenylacetic acids, esters, and metal salts are provided of the formula

wherein R represents a hydrogen atom or a lower alkyl group or sodium or potassium atom, R¹ represents a fluorine, chlorine or bromine atom or a lower-alkyl or amino group; R² represents a lower-alkyl, lower alkoxy, amino or trifluoromethyl group or a fluorine, chlorine or bromine atom; n is 0-3 and m is 0-2, or the pharmaceutically acceptable salts thereof or hydrates thereof. The compounds exhibit muscle relaxant activity, and are also useful as anti-inflammatory agents.

Description

TECHNICAL FIELD

The present invention relates to ravel biphenylacetic acids and is more particularly concerned with certain 2-amino-6-biphenylacetic acids, esters, and metal salts, compositions thereof, methods for the production thereof and use of the same.

BACKGROUND ART

Various biphenylacetic acids have been demonstrated to possess anti-inflammatory activity as disclosed in U.S. Patents 3,784,704 and 3,966,978. Bi^phenylacetic acids and esters having an amino substituent in the phenyl ring to which is attached the acetic acid moiety are disclosed in French Patent M 5,737. German Offenlegungs- schrift 2,355,084 discloses methyl 3-amino-4-bi^phenylace- tate as an intermediate in the preparation of phenanth- ridones.

DISCLOSURE OF THE INVENTION

According to one aspect of the present invention there is provided a compound having the structural formula:
wherein:

R represents a hydrogen atom or a lower alkyl group,
R¹ represents fluorine, chlorine, or bromine atom or a lower alkyl group or an amino group;
R² represents a lower alkyl, lower alkoxy, amino, or trifluoromethyl group or a fluorine, chlorine or brcmine atom;
n is O-3 and m is 0-3,

In another aspect of the present invention there is provided a therapeutic composition suitable for providing muscle relaxation comprising (a) an effective amount of a compound having the structural formula of Formula I and (b) a pharmaceutically acceptable carrier therefor.
The present invention also extends to compounds of Formula I for use in providing muscle relaxation in a living animal body with a minimum of undesirable side effects by internally administering to the said living animal body an effective amount of the said compound.
In still yet another aspect of the present invention there is provided a therapeutic composition suitable for alleviating inflammation comprising (a) an effective amount of a compound having the structural formula of Formula I, and (b) a pharmaceutically acceptable carrier therefor.
The present invention also extends to compounds of Formula I for use in alleviating inflammation in a li₇ing animal body with a minimum of undesirable side effects by internally administering to the said living animal body an effective amount of the said compound.
The novel compounds of this invention are useful as muscle relaxant and anti-inflammatory agents. The compounds may be administered alone or with suitable pharmaceutical carriers to warm blooded animals, mammals such as felines, canines and humans and can be in solid or liquid form as, for example, tablets, capsules, powders, solutions, suspensions or emulsions.
The compounds can be administered orally, parenterally, subcutaneously or intramuscularly. The unit dosage form can contain from about 1 to about 100 milligrams of a compound of this invention and can be administered in multiples thereof up to a daily dosage level of about 500 milligrams.
The solid unit dosage form can be a gelatin capsule containing a compound of this invention and a pharmaceutically acceptable filler or carrier such as sucrose, lactose or corn starch. Tablets containing the compounds represent another embodiment of this invention and may be prepared using conventional tableting materials.
The novel concept of the present invention resides in the provision of therapeutically active 6-biphenylacetic acids, esters and metal salts which have a primary amino group ortho to the acetic acid group. Therapeutically active compounds possessing such an arrangement have been heretofore unknown prior to the present invention.
The anti-inflammatory utility of the compounds of this invention was determined using a modification of the Evans Blue-Carrageenan Pleural Effusion Assay of Sancilio, L.F., J. Pharmacol, Exp. Ther. 168, 199-204 (1969).
The muscle relaxant utility of the compounds of the present invention was determined using the loss of righting test as set forth by A.P.Roszkowski, J. Pharmacol. and Expt. Therapeutics, Vol 192, page 75 (1960).
It has been surprisingly and unexpectedly found that the 2-amino-6-biphenylacetic acids of the present invention exhibit significant muscle relaxant activity, while 2-aminobiphenylacetic acids having the phenyl substituent in the 3 and 5 positions exhibit no such activity. The surprising muscle relaxant properties of the 2-amino-6-biphenylacetic acids is clearly shown in the following Table.
In the definition of symbols in the formulae hereof and where they appear elsewhere throughout this specification, the terms have the following significance.
The term "lower alkvl" as used herein means straight and branched chain radicals of un to six carbon atoms inclusive, preferably no more than four carbon atoms, and is exemplified by such groups as methyl, ethyl, propyl, isopropyl, butyl, sec. butyl, tertiary butyl, amyl, isoamyl and hexyl. The term "lower alkoxy" has the formula -0-lower alkyl.
When m = 2 or n = 2 or 3, R¹ or R² can be the same or different radicals.
Illustrative of pharmaceutically acceptable salts are the scdium, potassium, calcium, magnesium, zinc, and copper salts and the hydrates thereof.
The compounds of Formula I wherein R represents hydrogen may be prepared by hydrolysis of 4-^phenylindolin 2-ones (II) in aqueous basic solution followed by neutralization of the basic reaction mixture with a suitable organic acid such as acetic acid or a dilute acid as indicated by the following reaction scheme:
Formula II wherein R¹ and R² are as defined hereinabove.
The hydrolysis of a 4-phenylindolin-2-one (II) may be carried out in a dilute aqueous base as, for example, a 3N sodium hydroxide solution, for a period of from about 1.0 to about 60 hours, usually until the indolin-2-one has dissolved. The hydrolysis may be carried out in an inert atmosphere using nitrogen. The hydrolysis mixture may be filtered to remove base- insoluble materials and the pH of the basic solution is adjusted to a ^pH of from 6-7 by the addition of a weak organic acid such as glacial acetic acid or a dilute mineral acid such as hydrochloric acid.
The free acids can contain water of crystallization. Therefore the free acids containing various degrees of hydration are included within the scope of the present invention.
The lower alkyl esters of Formula I are preferably prepared from the acids which are converted to an alkali tetal salt, preferably the sodium or potassium salt which is isolated, dried, and then reacted in a suitable solvent as for example, dimethyl formamide, with an alkyl halide, preferably an alkyl iodide, to furnish the desired ester.
The 4-phenylindolin-2-ones (II) may be prepared from appropriately substituted biphenylamines (V) by the following reaction sequence, wherein R¹ and R have the values hereinabove defined except additionally R¹ and R² may be nitro in Formulas III, IV and V, and R represents a lower alkyl group, preferably an ethyl group. The reaction conditions employed are more fully set forth hereinafter in the specific preparations which follow.
Compounds of Formula II wherein R1 or _R ² represent an-NH₂ group may be prepared from the corresponding biphenyl amine wherein R¹ or R² represent an -N0₂ group, the resulting -N0₂ radical in Formula III being reduced by RaNi (Raney Nickel) or Sn/HCl at the same time as the methylthio group is removed. Additional reducing agent may be required and in the instance of tin, three additional moles per mole of-N0₂ are required as well as sufficient HC1 to maintain acid conditions.

BEST MODE OF CARRYING OUT THE INVENTION

The invention may be put into practice in various ways and a number of specific embodiments will be described to illustrate the invention with reference to the accompanying examples which are preceeded by preparations which describe the preparation of starting materials and intermediates for use in the examples.

Preparation 1

3-Methylthio-4-^phenylindolin-2-one

m-Biphenylamine hydrochloride (35.3g, 0.172 mole) was partitioned between 300 ml of methylene chloride and 200 ml of 5% sodium hydroxide solution. The layers were separated and the methylene chloride layer was dried (sodium sulphate) and its volume adjusted to 400 ml with additional methylene chloride. The solution was cooled to -65⁰C and 23.0g(0.172 mole) of ethyl 2-methylthioacetate were added. Immediately, 18.9g (0.175 mole) of t-butylhypochlorite were added dropwise. After the addition was completed, the mixture was stirred at -65 C for 1.5 hours, treated with 17.2g(0.125 mole) of triethylamine and allowed to warm up to ambient temperature. The methylene chloride solution was washed twice with two 100 ml portions of water, concentrated, and the residue dissolved in 200 ml of methanol. This solution was heated to reflux, treated with 40 ml of 3N hydrochloric acid and the mixture heated at reflux overnight. The dark solution was concentrated to approximately 100 ml, when a solid began to precipitate. The mixture was cooled, the solid collected by filtration, washed with a small volume of cold methanol and dried to give 22.8g(52%) of yellow material. A nuclear magnetic resonance (NMR) analysis of the material indicated that the solid was a mixture of the 4-phenyl isomer and the 6-phenyl isomer in a ratic of 2:1. The 4-phenyl isomer was separated from the 6-phenyl isomer by fractional crystallization from benzene. Three recrystallizations of the yellow solid from benzene gave 8.5g (19%) of 3-methylthio-4-phenylindolin-2-one as a white solid, m.p. 182-5⁰C.
Analysis: Calculated for C₁₅H₁₃NOS: C,70.56; H,5.13; N,5.49 Found : C,70.26, H,5.16; N,5.14

Preparation 2

4-Phenylindolin-2-one

A stirred solution of 3.5g (0.014 mole) of 4-phenyl-3-methylthioindolin-2-one in 75 ml of tetrahydrofuran was treated portionwise with 20g of a commercial Raney nickel/water suspension. The mixture was filtered through Celite (Registered Trade Marx) and the filtrate concentrated to give a yellow solid. This solid was recrystallized from benzene to yield 1.6g (57%) of product as an off-white solid. An analytical sample was prepared from isopropanol; m.p. 192-194°C.
Analysis: Calculated for C₁₄H₁₁NO: C,80.36; H,5.30; N,6.69 Found : C,80.52; H,5.41; N,6.72

Preparation 3

3-Methylthio-7-methyl-4-^phen^ylindolin-2-one

A solution of 30.6g (0.13 mole) of 3-amino-4-methylbiphenyl in 400 ml of methylene chloride was cooled to -65⁰C and treated witn 17.Og (0.13 mole) of ethyl 2-methylthioacetate and then 14.2g(0.132 mole) of t-butylhypochlorite while maintaining the temperature below -60°C. Tne reaction mixture was stirred at -65°C for 1.5 hours, treated with 13.3 (0.132 mole) of triethyl amine and allowea to warm up to ambient temperature. The solution was washed twice with water and concentrated. The residue was dissolved in 200 ml of methanol, 40 ml of 3N hydrochloric acid were added, and the mixture refluxed overnight. The solution was concentrated until a solid began to precipitate. The mixture was cooled, and the solid collected by filtration.

Preparations 4A to 4I

When in the procedure of Preparation 3 and in the manner of the preceding discussion, 3-amino-4-methylbiphenyl was replaced by equal molar amounts of the following:

3-amino-5-methylbiphenyl,
3-amino-2'-methoxybiphenyl,
3-amino-2',5'dimethoxybiphenyl,
3-amino-3'-chlorobiphenyl,
3-amino-3',5'-dibromobiphenyl,
3-amino-4-chlorobiphenyl,
3-amino-4,6-dichlorobiphenyl,
3-amino-6-methyl-2'-methylbiphenyl,
3-amino-2',4-dichlorobiphenyl,

3-methylthio-6-methyl-4-phenylindolin-2-one and 3-methylthio-4-methyl-6-phenylindolin-2-one, (4A)
3-methylthio-4-(2-methoxyphenyl)indolin-2-one and 3-methylthio-6-(2-methoxyphenyl)indolin-2-one, (4B)
3-methylthio-4-(2,5-dimethoxyphenyl)indolin-2-one and 3-methylthio-6-(2,5-dimethoxyphenyl)indolin-2-one, (4C)
3-methylthio-4-(3-chlorophenyl)indolin-2-one and 3-methylthio-6-(3-chlorophenyl)indolin-2-one, (4D)
3-methylthio-4-(3,5-dibromophenyl)indolin-2-one and 3-methylthio-6-(3,5-dibromophenyl)indolin-2-one, (4E) 3-methylthio-7-chloro-4-phenylindclin-2-one, (4F) 3-methylthio-5, 7-dichloro-4-phenylindolin-2-one,(4G) 3-methylthio-5-methyl-4-(2-methylmenyl)indoline-2-one(4H) a 3-methylthio-7-chloro-4-(2-chlorochenyl)indolin-2-one. (4J).

Preparation 5

6-Methyl-4-phenylindolin-2-one

To a slurry of 11.8₉(0.044 mole) of 3-methylthio-6-methyl-4-phenylindoline-2-one in 500 ml of tetrahydrofuran were added 100g of a commercial Ranev nickel/water preparation portionwise over a two-hour period. The mixture was filtered through Celite (Re^gist- ered Trade Mark) and the filtrate concentrated. A small amount of methylene chloride was added to the residue and the resulting solid was collected by filtration.

Preparations 6A to 6J

When in the procedure of Preparation 5 and in the manner of the preceding dicussion, 3-methylthio-6-methyl-4-phenylindolin-2-one was replaced by equal molar amounts of the following methylthioindolin-2-ones: 3-methylthio-7-methyl-4-phenylindolin-2-one, 3-methylthio-6-methyl-4-phenylindolin-2-one, 3-methylthio-4-(2-methoxyphenyl)indolin-2-one, 3-methylthio-4-(2,5-dimethoxyphenyl)indolin-2-one, 3-methylthio-4-(3-chlorophenyl)indolin-2-one, 3-methylthio-4-(3,5-dibromophenyl)indolin-2-one, 3-methylthio-7-chloro-4-phenylindolin-2-one, 3-methylthio-5,7-dichloro-4-phenylindolin-2-one, 3-methylthio-4-(2-methylphenyl)indolin-2-one, and 3-methylthio-7-chloro-4-(2-chlorophenyl)indolin-2-one, there were obtained

7-methyl-4-phenylindolin-2-one, (₆A)
6-methyl-4-phenylindolin-2-one, (6_B)
4-(2-methoxyphenyl)indolin-2-one, (6_C)
4-(2,5-dimethoxyphenyl)indolin-2-one, (6D)
4-(3-chlorophenyl)indolin-2-one, (6E)
4-(3,5-dibromophenyl)indolin-2-one, (6F)
7-chloro-4-phenylindolin-2-one, (6G)
5,7-dichloro-4-phenylindolin-2-one, (6_H)
5-methyl-4-(2-methylpheriyl)indolin-2-one, (6I) and
7-chloro-4-(2-chlorophenyl)indolin-2-one. (6J)

Preparations 7A to 7C

When in the procedure of Preparation 3 and in the manner of the preceding discussion, 3-amino-4-methylbiphenyl was replaced by equal molar amounts of the following nitro derivatives:

3-amino-3'-nitrobiphenyl,
3-amino-2'-nitrobiphenyl,
3-amino-4,6-dinitrobiphenyl,
there were obtained.
3-methylthio-4-13-nitrophenyl)indolin-2-one, and 3-methylthio-6-(3-nitrophenyl)indolin-2-one, (7A)
3-methylthio-6-(3-nitrophenyl)indolin-2-one, and 3-methylthio-6-(2-nitrophenyl)indolin-2-one, (7B) and
3-methylthio-4-phenyl-5,7-dinitroindolin-2-one (7C)

Preparation 8

4-Phenyl-5,7-diaminoindolin-2-one

A mixture of 4.9g (0.014 mole) of 3-methylthio-4-phenyl-5,7-dinitroindolin-2-one (see Preparation 7C), 4.2g (0.035 mole) of tin powder, 10 ml of concentrated hydrochloric acid and 50 ml of ethanol were refluxed for 4 hours under nitrogen. The hot mixture was filtered and the filtrate concentrated to give a solid.

Preparations 9A and 9B

When in the procedure of Preparation 8 and in the manner of the preceding discussion, 3-methylthio-4-phenyl-5,7-dinitroindolin-2-one was replaced by equal molar amounts of the following nitro-methylthioindolins of Preparation 7:

3-methylthio-4- (3-nitrophenyl)indolin-2-one, (see 7A)
3-methylthio-4-(2-nitrophenyl)indolin-2-one, (see 7B)

4-(3-amino^phenyl)indolin-2-one, (9A) and
4-(2-aminophenyl)indolin-2-one (9B).

Example 1

2-Amino-3-methyl-6-bi^phenvlacetic Acid Hydrate (1:4)

A mixture of 4.79g (0.0215 mole) of 7-methyl-4-phenylindolin-2-one (see Preparation 6A) and 60 ml of 3N sodium hydroxide was heated at reflux under nitrogen for 17 hours. The reaction mixture was cooled, filtered, and the filtrate diluted with 60 ml of water. The solution was cooled, made acidic with glacial acid and the resulting solid immediately collected by filtration, washed with cold water and dried under vacumm.

Example 2

2-Amino-6-biphenylacetic Acid

A mixture of 1.5g (0.007 mole) of 4-phenylindolin-2-one (see Preparation 2) and 20 ml of 3N sodium hydroxide was heated at reflux for 6 hours. The mixture was cooled and filtered. The filtrate was made acidic with glacial acetic acid, and the resulting solid collected by filtration, washed with water and dried to yield 0.5 g (32%) of product as a tan powder, m.p. 190-191°C (dec.).
Analysis: Calculated for C₁₄H₁₃NO₂: C,73,99; H,5.77: N,6.16 Found : C,73.54; H,5.71; N,6.28

Example 3

Sodium 2-amino-6-biphenylacetate

A solution of 2.8g (0.0125 mole) of crude 2-amino-6-biphenylacetic acid in 40 ml of tetrahydrofuran was treated with 2 ml of 5% sodium hydroxide. The solution was concentrated and the residue subject to a benzene azetrope to eliminate water. The resulting tan solid was recrystallized three times from ethyl alcohol to give a pure sample of the sodium salt as a tan solid, m.p. 128-48°C. (dec.)
Analysis: Calculated for C₁₄H₁₂NaNO₂: C,67.46; H,4.85; N,5.62 Found :C,67.25; H,4.96; N,5.65

Example 4

When in the procedure of Example 1 and in the manner of the preceding discussion, 7-methyl-4-phenylindolin-2- one was replaced by equal molar amounts of

5-methyl-4-(2-methylphenyl)indolin-2-one (see 6I) there was obtained
2-amino-5,2'-dimethyl-6-biphenylacetic acid.

Examples 5A and 5B

When in the procedure of Example 1 and in the manner of the preceding discussion, 7-methyl-4-phenylindolin-2-one was replaced by equal molar amounts of

4-(2-methoxyphenyl)indolin-2-one, (see 6C)
4-(2,5-dimkthoxvphenyl)indolin-2-one (see 6D) there were obtained
2-amino-2'-methoxy-6-bi^phenylacetic acid (Example 5A).
2 amino-2',5-dimethoxv-6-biphenylacetic acid (Example 5B)

Examples 6A and 6B

When in the manner of Example 1 and in the manner of the preceding discussion, 7-methyl-4-phenylindolin-2- one was replaced by equal molar amounts of 4-(3,5-dibromophenyl)indolin-2-one, (see 6F) 7-chloro-4-(2-chlorophenyl)indelin-2-one, (see 6J) there were obtained

2-amino-3',5'-dibromo-6-bi_Dhenylacetic acid, (Example 6A)
2-amino-2',3-dichloro-6-biphenylacetic acid (Example 6B)

Examples 7A and 7B

When in the procedure of Example 1, 2 moles of potassium hydroxide per mole of the indolin-2-one was substituted for the sodium hydroxide, ethanol was substituted for water and 7-methyl-4-phenylindolin-2-one was replaced by equal molar amounts of

4-(3-aminophenyl)indolin-2-one, (see 9A)
4-(2-aminophenyl)indolin-2-one (see 9B) there were obtained
2,3'-diamino-6-biphenylacetic acid (Example 7A)
2,2-diamino-6-biphenylacetic acid (Example 7B)

Example 8

When in the procedure of Example 1, 2 moles of potassium hydroxide per mole of the phenylindolin-2-one was substituted for the sodium hydroxide, ethanol was substituted for water and 7-methyl-4-phenylindolin-2-one was replaced by equal molar amounts of

4-phenyl-5,7-diaminoindolin-2-one (see 8) there was obtained
2,3,5-triamino-6-biphenylacetic acid.

Examples 9A to 9D

When in the procedure of Example 1 and in the manner of the preceding discussion, 7-methyl-4-phenylin- dolin-2-one was replaced by equal molar amounts of

6-methyl-4-phenylindolin-2-one (see 6B)
4-(3-chlorophenyl)indolin-2-one (see 6E)
7-chloro-4-phenylindolin-2-one (see 6G)
5,7-dichloro-4-phenylindolin-2-one, (see 6H) there were obtained
2-amino-4-methyl-6-bi^phenylacetic acid (Example 9A)
2-amino-3'-chloro-6-biphenylacetic acid (Example 9B)
2-amino-3-chloro-6-biphenylacetic acid (Example 9C)
2-amino-3,5-dichloro-6-biphenylacetic acid (Example 9D).

Example 10

Ethyl 2-Amino-G-bi^phen^ylacetate

Sodium 2-amino-6-bi^phenylacetate was dissolved in dimethylformamide and the solution treated with ethylio- dide. The solution was stirred at room temperature for about 3 hours, the solution added to water and the mixture extracted several times with benzene. The combined benzene extracts were washed with dilute base and water, dried over sodium sulphate, concentrated under reduced pressure and crystallized to give ethyl 2-amino-6-biphenylacetate.

Formulation and Administration

The present invention also contemplates compositions containing the compounds of the present invention as active ingredients. Effective quantities of any of the foregoing pharmacologically active compounds may be administered to a living animal body in any one of various ways. For example, they may be orally administered in the form of sterile solutions. In forming the compositions of this invention, the active ingredient is incorporated in a suitable carrier such as a pharmaceutical carrier. Suitable pharmaceutical carriers which are useful in formulating the compositions of this invention include starch, gelatin, glucose, magnesium carbonate, lactose, and malt. Liquid compositions are also within the purview of this invention and suitable liquid pharmaceutical carriers include ethyl alcohol, propylene glycol, glycerine, and glucose syrup.
The pharmacologically active compounds of the present invention may be advantageously employed in a unit dosage of from about 1 to about 100 milligrams. The unit dosage may be given a suitable number of times daily so that the daily dosage may vary from 1 to 500 milligrams. Five to 50 milligrams appears to be an optimum unit dose.
It is only necessary that the active ingredient constitute an effective amount; i.e. such that a suitable effective dosage will be obtained consistent with the dosage form employed. The exact individual dosages as well as daily dosages will, of course, be determined according to standard medical principles under the direction of a physician or veterinarian.
The active agents of the present invention may be combined with the pharmacologically active agents, or with buffers, antacids or the like for administration. The proportion of the active agent in the compositions may be varied widely.
The following are examples of compositions formed in accordance with this invention.

Examples 11A to 11C

Capsules of 5 mg, (Example llA), 25 mg (Example 11B), and 50 mg (Example 11C) of active ingredient per capsule were prepared. With the higher amounts of active ingredient, adjustment may be made in the amount of lactose.

Example 11A

Example 11B

Additional cansule formulations preferably contain a higher dosage of active ingredient and are as follows:-
In each case the selected active ingredient was uniformly blended with the lactose, starch, and magnesium stearate and the blend encapsulated.

Example 12

A typical formulation for a tablet containing 5.0 mg of active ingredient per tabletis as follows. The formulation may be used for other strengths of active ingredient by adjusting the weight of the dicalcium phosphate.
The tablets were formed by uniformly blending ingredients 1, 2, 4 and 5. Ingredient 3 was prepared as a 10 percent paste in water. The blend was granulated with starch paste and the resulting wet mass passed through an eight mesh screen (U.S. Sieve size), having openings of 2.4 mms. The wet granulations was dried and sized through a twelve mesh screen (U.S. Sieve size) having openings of 1.7 mms. The dried granules were blended with the calcium stearate and pressed.

Example 13

An injectable 2% sterile solution was made up as follows:-
The solution was prepared, clarified by filtration and placed into vials. The vials were sealed and heated in an autoclave.

Claims

1. A compound having the structural formula:-

wherein:

R represents a hydrogen atom or a lower alkyl group

R represents a fluorine, chlorine or bromine atom or a lower alkyl or amino group.

_R2 represents a lower alkyl, lower alkoxy, amion or trifluoromethyl group or a fluorine, chlorine or bromine atom,

n is O-3 and m is 0-2, or a pharmaceutically acceptable salt thereof or a hydrate thereof.

2. 2-Amino-6-biphenylacetic acid or a ^pharmaceut- ically acceptable salt thereof.

3. A compound as claimed in claim 1 in which R represents a methyl group or an amino group or a chlorine atom, and m = 1, and n = 0.

4. A compound as claimed in claim 1 in which m = 0, R² represents a methoxy group, an amino group, or a chlorine atom and n = 1.

5. A compound as claimed in claim 1 in which m = 2, R represents an amino group or a chlorine atom and n = 0.

6. A compound as claimed in claim 1 in which m = ₀, R² represents a methoxy group or a bormine atom and n = 2.

7. A compound as claimed in claim 5 or claim 6 in which the R substituents are the same or the R² substituents are the same.

8. A muscle relaxation or inflammation alleviating composition comprising (a) as the active ingredient an effective amount of a compound as claimed in anyone of claims 1 to 7 and (b) a pharmaceutically acceptable carrier therefor.

9. A composition as claimed in claim 8 in which the effective amount ranges between 1 and 100 milligrams of the active ingredient.

10. A compound as claimed in anyone of claims 1 to 7 or a composition as claimed in claim 8 or claim 9 for use in muscle relaxation in a living animal body or for use in alleviating inflammation in a living animal body.